Abstract 6676: Exploratory biomarker analyses in phase 1 study of regorafenib, ipilimumab, and nivolumab (RIN) in chemotherapy resistant microsatellite stable (MSS) metastatic colorectal cancer (mCRC)
Authors: Jian Ye, Chongkai Wang, Colt Egelston, Weihua Guo, Peter P. Lee, Marwan Fakih
Journal: Cancer Research (2023)

Abstract Background: We recently reported an objective response rate of 36.4% in a phase I trial of RIN in MSS mCRC patients without liver metastases, while no response was noted in patients with liver metastases. Here we characterized kinetics in local and systemic immune responses associated with clinical outcomes, liver metastasis, and immune related toxicity during RIN treatment. Methods: Patients with chemotherapy-resistant MSS mCRC received RIN at (R) at 80 mg QD x 21 days in 4-week(w) cycle, (I) at 1mg/kg Q6w and (N) at 240 mg Q 2w (n=29). Needle biopsies were collected at baseline (n=8) and 4 weeks (n=6) after treatment. Blood samples were collected at baseline (n=29), 4 weeks (n=29) and 8 weeks (n=25) after treatment. Alterations in the tumor microenvironment (TME) were characterized by RNA sequencing. We analyzed the immune cell composition and activities in the blood, including 90 subpopulations of leukocytes and 29 activation/suppression/proliferation markers, with high-dimensional spectral flow cytometry. Results: The clinical responses are positively correlated with the induction of local anti-tumor immunity. Patients with better clinical outcomes exhibited higher levels of lymphocyte infiltration, chemokine production, and antigen-presentation potential in the local TME following one cycle of RIN treatment. The duration of progression-free survival (PFS) was correlated with a higher baseline STING signal in the TME. In the peripheral blood, the responders have more circulating CD4 T cells, B cells, and cDC1, while expressing lower immune activation markers, especially in T cells with type 1 immunity at baseline. At 4 weeks, immune activation and proliferation markers were higher in responders than non-responders. Interestingly, immune effectors (non-Tregs, CD45RA− CD8 T cells, NKT cells, and M1 monocytes) in the blood were proportionally reduced in responders at 4 weeks, coincident with their enrichment in the local TME. We also compared peripheral immune signatures between patients with and without liver metastases, liver metastases (n=7) were associated with a significantly lower ratio of CD4/CD8 T cells in the blood, a phenomenon of immunosenescence, both at baseline and after RIN treatment. Lastly, the occurrence of immune-related toxicities was closely correlated with the induction of immune activities in both acellular and cellular components in the circulation. Conclusions: Clinical benefit of RIN was correlated to more robust immune activation of the TME and peripheral blood following one cycle of treatment. A higher baseline STING signal in the TME was associated with longer PFS. Liver metastasis was associated with a lower ratio of peripheral CD4/CD8 T cells which may contribute to the resistance to immunotherapy in those patients. Citation Format: Jian Ye, Chongkai Wang, Colt Egelston, Weihua Guo, Peter P. Lee, Marwan Fakih. Exploratory biomarker analyses in phase 1 study of regorafenib, ipilimumab, and nivolumab (RIN) in chemotherapy resistant microsatellite stable (MSS) metastatic colorectal cancer (mCRC). [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6676.